Forced homo-oligomerization of RARα leads to transformation of primary hematopoietic cells
Forced homo-oligomerization of RARα leads to transformation of primary hematopoietic cells
复制标题
DOI：
10.1016/j.ccr.2006.01.005
复制
发表时间：
2006-02-01
期刊：
影响因子：
50.3
通讯作者：
So, CWE
中科院分区：
文献类型：
--
作者：
Kwok, C;Zeisig, BB;So, CWE
几乎100%的APL患者携带嵌合转录物，编码截断的RAR α融合到来自伴侣蛋白的同源寡聚结构域。为了进一步了解RAR α融合蛋白介导的细胞转化机制，我们进行了全面的结构/功能分析，并确定了POZ同源寡聚化结构域是PLZF-RAR α介导的原代造血细胞体外转化所必需和充分的最小转化结构域。合成的fkbp寡聚化结构域可以挽救一个同源寡聚化缺陷但没有共抑制因子相互作用缺陷的转化不能力的PLZF-RAR α突变体。此外，人工构建的FKBP-RAR α不仅模拟了真正的RAR α融合蛋白的各种生化特性，而且还介导了atra依赖性转化。综上所述，这些发现支持了RAR α介导转化的寡聚化依赖机制，并提出了分子治疗的潜在途径。
Almost 100% of APL patients carry chimeric transcripts encoding truncated RAR alpha fused to homo-oligomerization domains from partner proteins. To gain further insights into the cellular transformation mechanisms mediated by RAR alpha fusion proteins, thorough structure/function analyses have been performed and identified the POZ homo-oligomerization domain as the minimal transformation domain that is necessary and sufficient for PLZF-RAR alpha-mediated in vitro transformation of primary hematopoietic cells. A transformation-incompetent PLZF-RAR alpha mutant defective in homo-oligomerization but not corepressor interaction could be rescued by synthetic FKBP-oligomerization domains. Furthermore, an artificial FKBP-RAR alpha construct not only mimicked various biochemical properties of bona fide RAR alpha fusion proteins but also mediated an ATRA-dependent transformation. Taken together, these findings endorse an oligomerization-dependent mechanism for RAR alpha-mediated transformation and suggest a potential avenue for molecular therapy.